[unreadable] Neural tube defects (NTDs) occur at an incidence of 1/1000 births in the United States. The predisposition to and development of NTDs is complex with both genetics and environmental components implicated. This proposal is designed to evaluate one large multiplex NTD Family 8776 that is thought to harbor a strong genetic effect to reveal important disease-associated variants. A microsatellite genome-wide screen of forty-four multiplex families demonstrated evidence for linkage on chromosomes 7 and 10, with the results on chromosome 7 being driven primarily by Family 8776. A high density, whole-genome single nucleotide polymorphism (SNP) screen was performed on this family revealing significant regions of linkage to the subtelomeres of chromosomes 2 and 7. Since the telomeres are subject to increased recombination events, we will perform comparative genomic hybridization (CGH) and cytogenetic subtelomeric fluorescence in situ hybridization (FISH) to investigate for potential microdeletions and/or translocation events. Fine mapping and haplotyping will be conducted on 2q33.1-q35 and 7p21.1-22.3 to determine the minimum candidate gene interval. Candidate genes will be prioritized based on biological plausibility, expression studies, and bioinformatics methods. The genetic variant(s) identified for Family 8776 will be tested on a large cohort of NTD pedigrees using family-based association methods. Potential gene-gene and gene-environmental interactions will be investigated on Family 8776 and our large NTD dataset. [unreadable] [unreadable] [unreadable]